In general, the development of new therapeutic agents for treating CNS diseases is often severely hindered by the inability of many substances to enter the brain from the bloodstream. However, since motor neurons have numerous axon terminals located outside the blood-brain barrier, it may be possible to exploit these portals to selectively deliver therapeutic substances to these nerve cells when they are injured or diseased. The purpose of this project is to study the efficacy of two recombinant hybrid proteins as agents for the targeted delivery of potentially therapeutic proteins to CNS neurons (particularly motor neurons). These hybrid proteins, SOD:Tet45l and SMN:Tet45l, were respectively engendered to combine the neuron targeting properties of tetanus toxin fragment C with the putative neuroprotective effects of either 1) human superoxide dismutase (SOD-1), an antioxidant enzyme, or 2) survival motor neuron (SMN) protein, a novel protein whose absence or loss of function may be involved in the spinal muscular atrophies. The experiments outlined in this proposal are designed to test the potential neuroprotective ability of these hybrid proteins in vitro and in vivo.